-
Progress in understanding systemic lupus erythematosus (SLE) has
been hampered by disease heterogeneity. Patients with SLE can
present with diverse organ involvement as well as diverse
autoantibodies. In fact, SLE probably represents several
heterogeneous diseases that fall into a broad clinical phenotype of
systemic autoimmunity. Many patients with SLE have mild disease,
whereas others have a catastrophic presentation and lifethreatening
progression. Our current understanding of the factors that drive
the different phenotypes in SLE is limited; however, in spite of an
imperfect understanding of the pathogenesis of SLE, great progress
has been made over the past 50 years and mortality is now only
10% within 10 years (compared with 50% within 3 years in
the 1960s)1. Nevertheless, infections related to immune
suppression, cardiovascular disease, and renal failure constitute a
substantial burden, and medical costs and costs related to lost
productivity are high2.
The pathogenesis of SLE hinges on loss of tolerance and
sustained autoantibody production (FIG. 1). Unlike selflimited
autoantibody processes, such as autoimmune haemolytic anaemia, SLE
is generally a lifelong condition. One of the key concepts in
pathogenesis is an imbalance between apoptotic cell production and
disposal of apoptotic material (FIG. 2). Nuclear antigens are
typically not accessible to the immune system, but during the
course of apoptosis the cell membrane forms blebs that pinch off
from the cell and contain fragmented
cellular material, including nuclear antigens3. Such apoptotic
debris is normally cleared rapidly and would not be accessible to
the immune system. In humans, approximately 1 billion neutrophils
undergo apoptosis every day and increases in the apoptotic cell
load can be generated by exposure to ultraviolet light, infections,
and toxins, which are all known to be associated with SLE.
Persistent apoptotic debris containing nucleic acids can stimulate
an inflammatory response through the activation of nucleic acid
recognition receptors, such as members of the Tolllike receptor
(TLR) family4. Circulating apoptotic microparticles also prime
neutrophils for extrusion of nuclear material, providing yet more
antigen5. Nucleic acid recognition receptors control endogenous
retroviruses, recognize viral pathogens, and defend against
intracellular bacteria, and are strongly associated with
type I interferon (IFN) production. Defects in these pathways
are now strongly implicated in the pathogenesis of SLE, as both
increasing disease susceptibility and directly causing monogenic
forms of SLE (TABLES 1,2).
Type I IFNs and other cytokines promote Bcell
differentiation and loss of tolerance. B cells can respond to
nucleic acids through direct antigen recognition and via surface
IgM receptors for proteins complexed with nucleic acids. Once
autoantibodies have formed, B cells can also take up nucleic
acids through Fc receptors and Bcell receptors recognizing Fc
(rheumatoid factor)6. Once activated, these B cells mature,
expand, and begin
1Division of Rheumatology, Beth Israel Deaconess Medical Center,
Harvard Medical School, 110 Francis Street, Boston, Massachusetts
02215, USA.2Division of Immunology, Boston Children’s Hospital,
Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts
02115, USA.3Department of Pediatrics, Lisbon Medical School, Lisbon
University, Santa Maria Hospital, Avenida Professor Egas Moniz,
1649–035 Lisbon, Portugal.4Division of Allergy and Immunology, The
Children’s Hospital of Philadelphia, The University of Pennsylvania
Perelman School of Medicine, 3615 Civic Center Boulevard,
Philadelphia, Pennsylvania 19104, USA.
Correspondence to: K.E.S. [email protected]
doi:10.1038/nrrheum.2016.186Published online 22 Nov 2016
New insights into the immunopathogenesis of systemic lupus
erythematosusGeorge C. Tsokos1, Mindy S. Lo2, Patricia
Costa Reis3 and Kathleen E. Sullivan4
Abstract | The aetiology of systemic lupus erythematosus (SLE)
is multifactorial, and includes contributions from the environment,
stochastic factors, and genetic susceptibility. Great gains have
been made in understanding SLE through the use of genetic variant
identification, mouse models, gene expression studies, and
epigenetic analyses. Collectively, these studies support the
concept that defective clearance of immune complexes and biological
waste (such as apoptotic cells), neutrophil extracellular traps,
nucleic acid sensing, lymphocyte signalling, and interferon
production pathways are all central to loss of tolerance and tissue
damage. Increased understanding of the pathogenesis of SLE is
driving a renewed interest in targeted therapy, and researchers are
now on the verge of developing targeted immunotherapy directed at
treating either specific organ system involvement or specific
subsets of patients with SLE. Accordingly, this Review places these
insights within the context of our current understanding of the
pathogenesis of SLE and highlights pathways that are ripe for
therapeutic targeting.
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mailto:sullivak%40mail.med.upenn.edu?subject=mailto:sullivak%40mail.med.upenn.edu?subject=http://dx.doi.org/10.1038/nrrheum.2016.186
-
to secrete more antibody, which enhances the adaptive immune
response. Tcell and Bcell abnormalities have long been described in
SLE and are thought to be central to the disease process. The
autoantibodies identified in SLE are generally highaffinity,
somatically mutated IgG, which suggests that they have arisen in
germinal centres, where T cells provide help for class
switching.
This framework for understanding SLE has been our model for the
past ten years. It is founded on genetic data, in vitro
analyses, and observations in mouse models. In this Review, we
cover new insights that extend this model and offer the potential
for novel therapeutic interventions in SLE. We discuss
environmental and genetic factors that contribute to the risk of
developing SLE, and examine how gene expression and regulation
contributes to the phenotype of the disease and how these effects
provide a window into the clinical features. Subsequent sections
investigate mechanisms as we understand them from a cell biology
perspective, and three examples of local tissue effects that can
contribute to organ damage and modulate disease are also presented
(FIG. 1).
Environmental risk factorsImperfect disease concordance between
monozygotic twins suggests that environmental factors influence the
pathogenesis of SLE. Hormones and ultraviolet light have long been
recognized as contributors to SLE7,8. Women comprise 90% of most
SLE cohorts, and oestrogen and prolactin enhance immune responses
through diverse mechanisms9,10. Ultraviolet light is thought to
drive apoptosis, providing an immunologic stimulus. A possible
connection between sunlight exposure and druginduced lupus has also
been identified. Ultraviolet light converts propranolol into a
proinflammatory aryl hydrocarbon receptor ligand, possibly
explaining its association with lupuslike disease11.
Infections have been implicated in SLE for many years.
Epstein–Barr virus and cytomegalovirus are considered to be SLE
triggers12, whereas Helicobacter pylori13, hepatitis B virus14, and
parasite infections are thought to be protective15. One study found
that herpes simplex virus type 2 transcripts were
overexpressed in patients with systemic autoimmune diseases,
although the role of immunosuppression in increased viral gene
expression could not be eliminated16. Further data support a role
for microorganisms in general. Lipopolysaccharide is a component of
the cell wall of Gramnegative bacteria that can activate TLR4.
Serum levels of lipopolysaccharide are increased in patients with
SLE17 and bio markers of lipopolysaccharide engagement by TLR4,
such as shedding of CD14, correlate with disease activity18.
TLR4 activation promotes disease in mouse models of lupus19.
Microbial stimulation of myeloid cells by TLRs is critical for
antigen presentation to T cells20. These data suggest that
chronic microbial translocation contributes to the pathogenesis of
SLE. Bacterial biofilms represent another mechanism by which
microorganisms interact with the immune system. Amyloid–DNA
complexes, found in many biofilms, greatly increased the production
of autoantibodies in lupusprone mice21. At this point, the evidence
seems clear that SLE is not uniformly caused by a single infection,
but the role of bacteria and viruses generally in SLE represents an
emerging area of study, and TLR antagonists are being evaluated as
therapeutic agents.
The microbiome represents the collection of bacteria, viruses,
and fungi that coexist on and in the human body. Collectively,
microbial cells far outnumber human cells within the body and,
while many were previously thought to be silent passengers, we now
know that some can modulate the immune system22. Interest in the
microbiome has grown exponentially, as it represents an attractive
therapeutic target. In women with SLE, a lower Firmicutes to
Bacteroidetes ratio was seen than in healthy individuals, even
during times of remission23. In humans, microbiome studies are
largely correlative, but mouse studies support a mechanistic role
for the microbiome. Increased levels of Bacteroidetes were also
seen in lupusprone mice24. In a separate study, a manipulation that
aimed to normalize the microbiome was beneficial in MRL/lpr mice25.
The mechanism of the effect is not fully understood, but certain
gut bacteria foster the development of regulatory T cells
(Treg cells)26,27. Developing the ‘correct’ (that is, healthy)
microbiome might require neonatal exposure; one study found that
development of antinuclear antibodies was dependent on bacterial
colonization during the neonatal period in mice28. Although
therapeutic alteration of the microbiome in humans has been limited
to the setting of infections and inflammatory bowel disease, these
studies represent an important proof of concept for the pursuit of
additional studies in patients with SLE.
Genes and gene expressionOne of the great advantages of pursuing
genetic analyses in a highly heterogeneous disorder such as SLE is
that it is otherwise difficult to understand which facets of
disease represent susceptibility features, and which represent
consequences of the disease.
Heritability of SLE and genetic studiesThe heritability of SLE
has long been recognized; a higher concordance rate in monozygotic
twins than in dizygotic twins and the high sibling recurrence risk
ratio support a strong heritability29. The major histocompatibility
complex (MHC) was the first risk locus to be associated with SLE,
and alleles within the MHC locus still confer the strongest genetic
susceptibility for SLE in the general population today30. This
seminal finding supports a disease process in which T cells
play a central part, as their activation is dependent on MHC
proteins (FIG. 2). In the past decade, numerous genomewide
Key points
• Our understanding of the pathogenesis of systemic lupus
erythematosus (SLE) has changed rapidly over the past decade
• Refinements in our understanding over the past 3 years
have led to the potential for precision targeting of therapeutic
strategies
• Advances in epigenetic therapeutic agents and the manipulation
of cells ex vivo have the potential to further improve patient
care
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Asymptomatic Autoantibodies Symptoms
Nature Reviews | Rheumatology
Genetics Susceptiblestate
• Hormones• Microbes• Ultraviolet
light• Diet• Toxins• Stochasticeffects
?TriggersLoss oftolerance
Spread ofautoimmunity
Local tissue contributions to inflammation
Self-sustainingfeed-forward loop
• Type I IFN• TNF• IL-6• Epigenetic changes• Tissue damage
association studies (GWAS) have been performed and we now
recognize over 40 loci that are confirmed to be associated with
SLE31. Variants rarely lie in the coding exons, however, and most
are instead thought to affect regulatory regions32. Regulatory risk
variants may affect proximal genes or may act at a distance through
chromosomal looping33; such variants might also have effects on
multiple genes.
Genes associated with SLE are listed in TABLE 1. The
overall genetic risks identified to date are limited, with each
gene generally conferring a relative risk
-
Nature Reviews | Rheumatology
• Recruitment ofinflammatory cells
• Tissue injury
Autoantibodies
• TNF• IL-6• IL-8
IL-17
Type I IFN
IL-21co-stimulation
IL-10
IL-6BAFF
Neutrophil
Myeloiddendritic cell
MacrophageApoptotic cell
T cell
B cell
Plasmacell
Antibodies tonucleic acids
Nucleic acids
Plasmacytoid dendritic cell
HMGB1
MHC
Antigenpresentation
TLR9 TLR7
BAFF-R
TACI
FcR
NET
CAMP
Type I IFN
histone modifications were measured and shown to be aberrant in
T cells from patients with SLE. These aberrations were
corrected by treatment with mycophenolate mofetil49. The second
approach utilized genomewide analyses. In the initial analysis,
histone H4 acetylation was shown to be globally increased in
monocytes from patients with SLE50. This finding is consistent with
those from DNA methylation studies51 because both DNA
hypomethylation and histone H4 hyperacetylation drive increased
expression of target genes. Within the sites with increased H4
acetylation, potential binding sites for IFN regulatory factor 1
(IRF1) were identified, and IRF1 binding was directly shown to be
increased in SLE52. IRF1 is a transcription factor downstream of
type I IFN, which ties this finding of an altered epigenome
back to the known influence of type I IFNs. Multiple histone
modifications in enhancer regions were globally altered in SLE
monocytes, which no doubt dictates altered cell behaviour53. Some
histone modifications persist after stimulation, thereby
‘bookmarking’ genes for facilitated reexpression. This feature
might contribute to disease chronicity54,55. One of the therapeutic
efforts directed at the epigenome utilizes inhibitors of
bromodomain containing protein 4 (BRD4), a protein critical for
enhancer function56. One such BRD4 inhibitor was demonstrated to
be effective in a mouse model of lupus57, again demonstrating the
power of these genomewide approaches to identify novel therapeutic
targets.
MicroRNA regulation in SLEMicroRNAs (mi RNAs) target specific
mRNAs for degradation and can regulate the abundance of multiple
mRNAs58. Changes in miRNA expression have been identified in
peripheral blood mononuclear cells and renal tissue from patients
with SLE59–61. Plasma mi RNAs can also be isolated and are presumed
to be released from cells as a result of death, stress, or
exocytosis62. Several of the mi RNAs identified in patients with
SLE seem to affect pathways that are central to the disease
processes of SLE61, such as TLR signalling and expression of
ISGs63. Expression of mi RNAs is very tissuespecific, and studies
of mi RNAs in kidney and peripheral blood samples from patients
with SLE, have found none in either tissue59,60. Other data from
human studies have implicated miR30a in B cells, where this
miRNA was thought to regulate expression of LYN, a critical
signalling molecule64. In MRL/lpr mice, overexpression of miR21 and
miR148a is responsible for the reduction in levels of
Figure 2 | Cellular contributions to the development of SLE.
Neutrophils and apoptotic cells are at the apex of the cascade of
pathogenetic mechanisms in systemic lupus erythematosus (SLE). They
provide the critical ligands to drive expression of type I
interferons (IFNs). Neutrophils represent a key inflammatory
participant in organ damage; these cells also release neutrophil
extracellular traps (NETs), a source of citrullinated peptide and
nucleic acid antigens, via NETosis. Many cells produce type I
IFNs, but plasmacytoid dendritic cells produce the highest levels
of these cytokines. Apoptotic debris can also activate inflammatory
cytokine expression which participates in the recruitment of cells
into tissues. T cells and B cells both participate in
autoreactivity, with B cells ultimately producing
autoantibodies. T‑cell production of IL‑17 also contributes to
organ infiltration by neutrophils. BAFF, B‑cell activating factor;
BAFF‑R, BAFF receptor; CAMP, cathelicidin antimicrobial peptide;
FcR, Fc receptor; MHC, major histocompatibility complex; TACI,
transmembrane activator and cyclophilin ligand interactor; TLR,
Toll‑like receptor.
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DNA methyltransferase 1 (DNMT1), an enzyme that creates
epigenetic changes by DNA hypomethylation65. The influence of mi
RNAs was demonstrated when a transgenic mouse overexpressing
miR1792 spontaneously developed lupuslike disease. The mechanism
seemed to be diminished expression of TFH cell regulators
phosphatidylinositol 3,4,5trisphosphate 3phosphatase and
dualspecificity protein phosphatase PTEN and PH domain leucinerich
repeatcontaining protein phosphatase 2 (REFS 66,67).
Deficiency of miR155 in MRL/lpr mice suppresses lupus, indicating
that the effects of mi RNAs are contextspecific and sitespecific,
as would be expected68. In addition to studying the role of mi RNAs
in the pathogenesis of SLE, researchers are showing increasing
enthusiasm for using these stable nucleic acids as biomarkers. For
example, miR21 regulates lymphocyte signalling, and levels of miR21
in T cells correlate with SLE disease activity index (SLEDAI)
scores69. The first miRNAbased therapeutic agent was approved in
2013 for the treatment of familial hypercholesterolaemia70, and
this field is likely to expand rapidly.
Differences in gene expressionTranscript abundance represents
the final balance between active transcription and mRNA turnover,
and integrates both transcript production and destruction effects.
Levels of transcripts ultimately control cell activities. Early
studies of gene expression were performed on peripheral blood
mononuclear cells or whole blood and uniformly identified a set of
ISGs71–73. Inflammatory and granulocyte signatures were also seen.
These pivotal studies, now over ten years old, led to focused
efforts on understanding the role of type I IFN and
neutrophils. Gene expression has been examined in sorted cells from
patients of varied ancestry74; ISGs could be identified in each
cell population but the expression of specific genes varied
dramatically between cell types, as well as between people of
different ancestry74. This study is an important reminder that our
current understanding of ethnic and population differences is
disappointingly rudimentary. Array studies on human T cells
have shown changes in gene expression related to disease activity
and
clinical presentation75–77. In oncology, arrays and other
measures of gene expression are now routinely used to stratify
patients’ level of risk and direct therapy. Their use in
rheumatology has been limited to research efforts, but a study
utilizing advanced informatics found clear disease activity
profiles78. Clinical use of gene expression for disease profiling
could, therefore, become a reality in rheumatology clinics.
Apoptosis and nucleic acid sensorsAberrant apoptotic cell
clearanceThe dysregulation of apoptosis and nuclear debris
clearance that is characteristic of SLE contributes to an increase
in autoantigen exposure3. The imbalance in apoptotic cell
production and clearance is highly influenced by infection,
ultraviolet light exposure, and cytokines. Accumulated apoptotic
debris can trigger TLRs and nucleic acid sensors. Immune cells,
including B cells, some T cells, dendritic cells (DCs),
and macrophages, as well as nonimmune cells, such as epithelial
cells and fibroblasts, express TLRs. Several pathways have evolved
to prevent immune activation in response to endogenous cellular
debris. Apoptotic cells become coated with complement component
C1q, Creactive protein, pentraxin 3, and serum amyloid P, which
enhances phagocytosis without immune stimulation79,80.
Additionally, DNase I contributes to degradation of chromatin79.
Decreased DNase I activity has been described both in patients with
SLE and in lupusprone mice81. Characterization of the pathogenesis
of monogenic forms of SLE has emphasized the role of aberrant
apoptotic clearance. Sequencing analysis of seven consanguineous
families with highly penetrant, auto somal recessive lupuslike
disease identified inactivating mutations in DNASE1L3
(REF. 82). Another family with a Mendelian pattern of SLE
inheritance was found to carry lossoffunction mutations in PRKCD,
which encodes the enzyme protein kinase Cδ83. This enzyme is
activated in multiple apoptotic pathways. These rare monogenic
diseases represent useful models of SLE because the disease process
can be clearly defined. Although affected patients often have a
phenotype that is not typical of classic SLE, they provide
important insights.
Table 1 | GWAS-identified SLE susceptibility genes
Pathway(s) Loci implicated in SLE and other autoimmune diseases
Loci implicated only in SLE
Lymphocyte activation
PTPN22, TNFSF4, IL10, SPRED2, STAT4, PXK, AFF1, IL12A, BANK1,
TCF7, SKP1, MHC genes, IKZF1 and IKZF3, BLK, ARID5B, CD44, LYN,
ETS1, FLI1, SH2B3, CSK, ELF1, CIITA, ITGAM, TYK2
IKZF2
IFN or Toll‑like receptors
IFIH1, PRDM1, UHRF1BP1, TNFAIP3, IRF5‑TNPO3, IRF7 and IRF8,
SOCS1, PRKCB, UBE2L3, IRAK1
None
Inflammation TNIP1 None
Immune complex or waste clearance
FCGR2A, FCGR2B, FCGR3B, ATG5, CLEC16A NCF2, LYST
Unknown ABHD6 (may be related to lymphocyte activation), RAD51B
(may be related to IFN pathways), MECP2 (may be related to IFN
pathways), RASGRP3, TMEM39A, PITG1, TNXB, JAZF1, XKR6, FAM167A–AS1,
WDFY4, unknown genes: rs1167796, rs463128, rs7186852, rs7197475
SMG7 (may be related to interferon pathways), DHCR7, NADSYN1,
SLC15A4, PLD2, CXorf21
GWAS, genome‑wide association studies; IFN, interferon; MHC,
major histocompatibility complex; SLE, systemic lupus
erythematosus.
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Role of TLRsApoptotic cells are cleared largely by cells in the
reticuloendothelial compartment. Clearance is generally silent but
when the burden of apoptotic cells exceeds that which can be
cleared, the apoptotic debris can elicit immune responses84. Mouse
models have been instrumental in defining the role of TLRs in
lupus; however,
extrapolation of findings from these models to humans is
controversial because not all features are consistent with our
current understanding of SLE in humans. Nevertheless, in the
analysis of specific pathways, mouse models of lupus offer great
advantages. Collectively, they have provided confirmation of the
importance of TLR trafficking.
Table 2 | Monogenic causes of SLE and lupus-like disease
Gene Effect Features Pathway Refs
C1QA, C1QB, C1QC
Complement C1 deficiency Early‑onset, severe SLE, infections;
high penetrance*; AR Immune complex and waste clearance
210,211
C1R, C1S Complement C1 deficiency Early‑onset, severe SLE,
infections; high penetrance; AR Immune complex and waste
clearance
212,213
C4A, C4B Complement C4 deficiency Early‑onset, severe SLE,
infections; high penetrance; AR Immune complex and waste
clearance
214
C2 Complement C2 deficiency Infections, cutaneous disease;
moderate penetrance; AR Immune complex and waste clearance
215
C3 Complement C3 deficiency Membranoproliferative
glomerulonephritis; low penetrance; AR
Immune complex and waste clearance
216
CYBB X‑linked chronic granulomatous disease
Infections, chronic granulomatous disease; low penetrance;
X‑linked
Immune complex and waste clearance
217
PEPD Xaa‑Pro dipeptidase deficiency Cutaneous ulcers; low
penetrance; AR Immune complex and waste clearance
218
MAN2B1 Lysosomal α-D-mannosidase (laman) deficiency
Hearing loss, dysostosis multiplex, progressive cognitive
decline; low penetrance; AR
Lysosomal oligosaccharide catabolism
219
TREX1 Aicardi–Goutières syndrome 1 Basal ganglia calcification,
brain atrophy, skin ulcers, fevers; high penetrance; AR or AD
Nucleic acid sensing; type I IFN
220,221
DNASE1 SLE High penetrance; AD Nucleic acid sensing 222
DNASE1L3 SLE 16 Early onset; high penetrance; AR Nucleic acid
sensing 82
SAMHD1 Aicardi–Goutières syndrome 5 Basal ganglia calcification,
brain atrophy, skin ulcers, fevers; high penetrance; AR
Nucleic acid sensing; type I IFN
223
ACP5 Spondyloenchondrodysplasia with immune dysregulation
Spondyloenchondrodysplasia, vitiligo, growth retardation; low
penetrance; AR
Nucleic acid sensing; type I IFN
224
RNASEH2A, RNASEH2B, RNASEH2C
Aicardi–Goutières syndrome 4, 2, and 3 respectively
Basal ganglia calcification, brain atrophy, skin ulcers, fevers;
high penetrance; AR
Nucleic acid sensing; type I IFN
225
ADAR Aicardi–Goutières syndrome 6 Basal ganglia calcification,
brain atrophy, skin ulcers, fevers; high penetrance; AR or AD
Nucleic acid sensing; type I IFN
226
IFIH1 Aicardi–Goutières syndrome 7 Basal ganglia calcification,
brain atrophy, skin ulcers, fevers; high penetrance; AD
Nucleic acid sensing; type I IFN
225
DDX58 Singleton–Merten syndrome 2 Dental loss, arterial
calcification, joint contractures; high penetrance; AD
Nucleic acid sensing; type I IFN
227
TMEM173 STING-associated vasculopathy, infantile-onset
Skin ulcers, interstitial lung disease; low penetrance; AD
Nucleic acid sensing; type I IFN
228
ISG15 Immunodeficiency 38, with basal ganglia calcification
Mycobacteria, intracranial calcification; low penetrance; AR
Nucleic acid sensing; type I IFN
229
PSMB8 Nakajo syndrome Fever, contractures, neutrophilic
dermatitis; low penetrance; AR
Immune complex and waste clearance; type I IFN
230
FAS, FASLG Autoimmune lymphoproliferative syndrome 1A and 1B,
respectively
Autoimmune cytopenias, adenopathy; high penetrance; AD
Lymphocyte signalling 231–233
PRKCD Autoimmune lymphoproliferative syndrome 3
Autoimmune cytopenias, adenopathy; moderate penetrance; AR
Lymphocyte signalling 83
PTPN11 Noonan syndrome 1 Short stature, cardiac anomalies; low
penetrance; AD Lymphocyte signalling 234
RAG1, RAG2 Several types of severe combined immune
deficiency
Infections, granulomas; low penetrance; AR Lymphocyte signalling
235,236
*Penetrance is indicted as a qualitative assessment of the
percentage of people with the condition who have features of
SLE.AD, autosomal dominant; AR, autosomal recessive; IFN,
interferon; SLE, systemic lupus erythematosus.
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TLR7 TLR9
Nature Reviews | Rheumatology
Type I IFN
SAMHD1
IFIH1 DDX58
MAVS
LRRFIP1
NOD2
IFI16 DDX41ADAR
TREX1STING(TMEM173)cGASDNA
RNA
Retroelementactivation
ExogenousEndogenous
cGAMP
StabilizetranscriptionNucleic acids
DNA
DNA viruses
Viruses
dsRNA pppRNA ssRNA
ssRNA
IRF3NF-κB
Endosome
TLR3, TLR7, TLR8 and TLR9 reside in the endoplasmic reticulum.
Transfer of TLRs to endosomes is regulated by the trafficking
protein unc93 homologue B1 (UNC93B1). The importance of
intracellular trafficking cannot be overstated, as it represents a
key regulatory strategy. In plasmacytoid DCs (pDCs), UNC93B1 sorts
large complexes of DNA into early endosomes, where TLR9 and IRF7
drive a strong IFN response. Small monomeric DNA is sorted into
late endosomes, where TLR9 and NFκB drive a proinflammatory
cytokine response85. Correct localization of TLRs limits their
access to selfantigens86. In pristanetreated mice, TLR7 (which
senses singlestranded RNA) was specifically required for the
production of RNAreactive autoantibodies and for the development of
glomerulonephritis87. Data from studies of pharmacologic or genetic
manipulation of TLR7 expression or function support a central role
for TLR7 in inflammation, loss of tolerance, and type I IFN
production88–91.
The relationship of TLR9 to SLE is more complex than that of
TLR7. TLR9 is a receptor for DNA containing unmethylated CpG
sequence motifs. SLE patients with active disease had a higher
number of TLR9expressing B cells and monocytes than did
patients with low disease activity, and levels of these cells
correlated with levels of antibodies to doublestranded DNA
(antidsDNA)92. In TLR9deficient lupusprone mice, the generation of
antidsDNA and anti chromatin autoantibodies was specifically
inhibited, while levels of other autoantibodies (such as antiSm)
were maintained or even increased93. However, in one lupus model,
TLR9 deficiency exacerbated disease
through a mechanism that might relate to competition with TLR7
for UNC93B1 (REF. 94). TLR3 and TLR8 also recognize RNA and
limited data support a role for these additional receptors in
susceptibility to SLE. These data have led to a model of SLE in
which TLRs engage nucleic acids and drive a type I IFN
response (FIG. 3).
Cytosolic nucleic acid sensorsCytosolic nucleic acid sensors
recognize viral infections and initiate defences focused on
type I IFN production. These sensors can also detect
endogenous ligands and elicit inflammation independent of
infection. Signalling pathways for these sensors converge on
stimulator of IFN genes protein (STING, encoded by TMEM173)95.
Additional protection from the deleterious effects of endogenous
nucleic acids comes from nucleases, which degrade nucleic acids.
Three cytosolic RNA helicases have been identified: probable
ATPdependent RNA helicase DDX58, interferoninduced helicase C
domaincontaining protein 1 (IFIH1, also known as MDA5), and
probable ATPdependent RNA helicase DHX58 (also known as LGP2).
These sensors act in the cytoplasm to complement the function of
endosomal TLRs96. The cytosolic sensors activate both IFN and
inflammatory cytokine production96. Variants in IFIH1 have been
linked to SLE97. Cytosolic DNA sensors also exist. All three main
types of inflammasomes can respond to DNA; however, the process
that drives these responses is not well understood (with the
exception of the AIM2 inflammasome, which is activated by STING)98.
Mouse models of lupus support a key role for this pathway in the
aetiopathogenesis of SLE99.
Figure 3 | Nucleic acid sensors in SLE. The importance of the
immune response to nucleic acids in systemic lupus erythematosus
(SLE) has been emphasized by data from mouse models and patients
with monogenic diseases associated with defects in these pathways.
Toll‑like receptors (TLRs) are restricted to vesicles and primarily
respond to endocytosed nucleic acids. Cytoplasmic sensors recognize
endogenous nucleic acids as well as a myriad of viruses. Responses
converge on two transcription factors, interferon regulatory factor
3 (IRF3) and nuclear factor‑κB (NF-κB), which are responsible for
the induction of type I interferon (IFN) expression as well as
some inflammatory cytokines.
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Nature Reviews | Rheumatology
Type I IFN• Apoptotic cells• Viruses• Retroelements
• Microbial translocation• Bacterial infection• Tissue damage•
Ultraviolet light
TNF
IL-6
IL-17
IL-10
BAFF
Neutrophil recruitment, monocyte activation
B-cell proliferation
Sustains type I IFN expression
Recruitment of inflammatory cells
B-cell proliferation, loss of tolerance
B-cell survival, T-cell activation
↓ Treg
cells — loss of tolerance
↑ NETs — IL-17, inflammation
↑ BAFF — B-cell proliferation, loss of tolerance
Here again, extraordinary insights have come from the study of
rare monogenic disorders with a lupuslike phenotype in humans.
Aicardi–Goutières syndrome has features that are reminiscent of a
congenital infection; however, this syndrome is caused by gene
defects that drive overproduction of type I IFN. Specifically,
mutations in genes encoding cytosolic nucleic acid sensors or their
regulators, such as TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1,
ADAR, or IFIH1, are all associated with this phenotype100
(TABLE 2). The Aicardi–Goutières phenotype has a more
prominent neurologic component than is typical of adultonset SLE;
however, autoantibodies are prolifically produced and some
pathologic features overlap with those of SLE100,101. In addition,
common variants in these same genes have been associated with SLE
(TABLE 1).
Soluble mediatorsCytokines can contribute to susceptibility to
SLE, but are more strongly implicated in loss of tolerance and
endorgan effects (FIG. 1). Levels of many cytokines are
elevated in SLE (such as TNF, IL4, IL6, and IL10) and their main
effects are the promotion of autoantibody production and
inflammation (FIG. 4). Type I and type II IFNs have
emerged as key cytokines in the pathogenesis of SLE (as well as
other autoimmune diseases) and increases in their levels precede
autoantibody development102,103. Upregulation of TNF can increase
type I IFN expression104,105. IFNα, a type I IFN
typically produced as part of the innate immune response to viral
infection, has multiple effects consistent with known immunologic
features of SLE, such as upregulation of Bcell activating factor
(BAFF, also known as TNF ligand super family member 13B or BLyS),
decreased Treg cell function, and induction of plasma cells106.
Transcripts of IFNα and ISGs have been detected in inflamed kidney
and skin tissues from patients with SLE107,108. A direct pathogenic
role for IFN in mouse models of lupus is also supported by studies
in which exogenous administration of IFNα exacerbates
disease109,110. Unfortunately, despite these
compelling data, clinical trials of IFN inhibitors have been
disappointing. Levels of two other cytokines, IL18 and IL38, are
also increased in SLE. IL18 is a potent proinflammatory cytokine
produced via the inflammasome, and IL38 is thought to be an
antiinflammatory cytokine with key regulatory functions111,112.
Patients with SLE may also have an imbalanced T cell
cytokine profile characterized by decreased IL2 and increased IL17
levels113. Production of IL2 is impaired on multiple levels114,115.
IL2, in addition to being critical for Treg cell development and
function, is also necessary for restricting expression of IL17. In
SLE, IL17 may mediate local tissue damage through the induction of
inflammatory cytokines and chemokines, and by recruiting other
immune cells. The differentiation of the T helper cell subset
producing IL17 (TH17 cells) is dependent on IL23, and an antiIL23
antibody ameliorated disease in one mouse model of lupus116.
Bcell activation and autoantibody production are promoted in SLE
by BAFF. Serum levels of BAFF are increased in patients with SLE
and positively correlate with autoantibody titres117. Transgenic
overexpression of BAFF in a mouse model of lupus exacerbated
disease118, emphasizing the role of this cytokine in supporting
autoimmunity. BAFF is a critical factor for Bcell homeostasis and
high BAFF levels might reduce the stringency of Bcell selection,
allowing autoreactive clones to persist in the periphery119.
Notably, Bcelldepletion therapy in patients with SLE is followed by
an increase in BAFF levels, raising concern that the repopulating
B cells could have a phenotype of increased autoreactivity120.
BAFF thus represents an important therapeutic target; indeed,
belimumab, an antiBAFF monoclonal antibody, is the first drug to be
approved for the treatment of SLE in more than 50 years121.
BAFFdirected therapy has demonstrated clinical efficacy but the
magnitude of the beneficial effect is modest, as has been true for
Bcelldepleting approaches122,123. The message might be that
narrowly targeted approaches in humans with established disease
cannot reverse pathologic downstream processes that have
Figure 4 | Cytokines implicated in SLE. Various stimuli that
have been epidemiologically associated with systemic lupus
erythematosus (SLE) can drive cytokine expression. Collectively,
the effects of this increased cytokine expression include both
inflammation and loss of tolerance. BAFF, B‑cell activating factor;
IFN, interferon; NET, neutrophil extracellular trap; Treg cell,
regulatory T cell.
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previously been initiated. Targeting of other cytokines is
nonetheless a priority for the pharmaceutical industry because
therapeutic monoclonal antibodies are an established pipeline.
Major cell types involved in SLEDendritic cellsInappropriate or
dysfunctional antigen presentation by DCs might promote the
breakdown of Tcell and Bcell tolerance in SLE and other autoimmune
diseases (FIG. 2). Patients with SLE show multiple DC
abnormalities, including a reduced number of circulating
conventional DCs, but increased numbers of pDCs124. The pDC subset
is the primary cell type responsible for type I IFN secretion
in response to nucleic acid, via TLR7 and TLR9. The pDCs take up
immune complexes via FcγRIIa and access TLR7 and TLR9 in the
endosomal compartment125. In SLE, conventional DCs promote
autoreactivity rather than tolerance126. In turn, activated
T cells also promote increased IFN production by pDCs127.
Conventional DCs have been demonstrated to be critical for the
development of lupus nephritis in a mouse model128. Thus, both
types of DCs are thought to be pivotal to the disease process
in SLE.
Myeloid cellsNeutrophils show several facets of dysregulation in
SLE. Impaired phagocytosis by neutrophils in SLE has been described
in multiple reports, and might contribute to the increased
susceptibility to infection associated with this disease129. In one
study, neutrophils from patients with SLE showed reduced production
of reactive oxygen species (ROS), which correlated with disease
severity and endorgan damage130. Patients with chronic
granulomatous disease, in which ROS production is defective, have a
high incidence of SLE131,132 (TABLE 2). Increased levels of
ISG products, autoantibodies, and glomerulonephritis have been
described in a mouse model of chronic granulomatous disease, and
lupusprone mice deficient in ROS production also show an
exacerbation of lupuslike disease133,134. Deficient ROS generation
might alter the apoptotic pathway, which connects this finding to
the recognized contribution of defective clearance of apoptotic
cells to the pathogenesis of SLE. Immune complexes can drive the
generation of mitochondrial ROS, and oxidized mitochondrial DNA can
be highly immunestimulatory, providing a feedforward loop135.
Neutrophils are shortlived and so represent the dominant cell type
in the daily burden of apoptotic cells. Small changes in neutrophil
apoptosis could markedly impact waste clearance. In an adoptive
cell transfer model, neutrophils from mice with chronic
granulomatous disease could drive autoantibody production in
control (diseasefree) recipient mice136. The converse was also
true; apoptotic neutrophils from control animals were capable of
driving autoantibody production when transferred to recipients with
chronic granulomatous disease. This study provides direct
mechanistic evidence for a central role of myeloid cells
in SLE.
Patients with SLE have an abnormal subset of neutrophils (termed
lowdensity granulocytes) with an increased propensity for
NETosis137. NETosis is a
mechanism of cell death that occurs in response to various
stimuli, including infectious organisms and oxidative stress.
NETosis involves the extrusion of chromatin and other nuclear,
cytoplasmic, and granular material from the cell (FIG. 2).
This extruded material, called neutrophil extracellular traps
(NETs), contains proinflammatory cytokines, antimicrobial peptides,
enzymes such as myeloperoxidase, and potentially antigenic
citrullinated histones and dsDNA138. NETosis contributes to the
type I IFN signature of SLE by stimulating IFN production by
pDCs137. This effect occurs via TLR9 activation by DNA and antiDNA
antibodies in complex with NETderived antimicrobial peptides such
as cathelicidin anti microbial peptide (also known as LL37)139,140.
In turn, type I IFN primes neutrophils for NET release in
patients with SLE, suggesting a possible positive feedback loop.
The extruded nuclear material from NETs represents a major source
of the nuclear antigens that drive autoantibody development
in SLE.
Monocytes from patients with SLE consistently have increased
baseline expression of CC chemokine ligand 2 (CCL2, also known as
monocyte chemoattractant protein 1 (MCP1))141. MCP1 is regulated by
lipopolysaccharide and IFNs, and is important in regulation of cell
migration. Monocyte infiltration into kidneys influences renal
damage, and monocyte infiltration into blood vessels contributes to
atherosclerosis, two key morbidities in SLE142,143. Renal
macrophage infiltration is a particularly strong prognostic
biomarker for progression of lupus nephritis144. Monocytes are,
therefore, a pivotal cell type in organ damage. Monocytedepletion
therapy was attempted in one clinical trial, which did not
demonstrate clinical effectiveness, but this approach did not
deplete tissue macrophages, which are thought to be important
drivers of endorgan damage in SLE145.
T cellsT cells are thought to be central to the
pathogenesis of SLE because of their association with MHC proteins,
and because adoptive transfer of these cells confers lupuslike
disease in some mouse models. Loss of Tcell tolerance is implied in
autoimmune diseases. Conceptually, this loss of tolerance could
happen centrally at the time of thymic education or peripherally;
however, mouse models support the importance of defects in
peripheral tolerance146. Deficient or defective Treg cells have
been identified both in mouse models and human studies147. GWAS
have also identified defects in lymphocyte signalling that could
centrally alter thymic deletion of autoreactive cells. Thus,
multiple pathways exist by which Tcell tolerance could be defective
in SLE. One of the first phenomena to be described was that of
aberrant signalling through the Tcell receptor. This phenomenon is
not cell intrinsic, and can be induced in normal T cells by
serum IgG from patients with SLE148. In T cells from patients
with SLE, the CD3 ζ chain (which mediates signalling via
tyrosineprotein kinase ZAP70) is downregulated owing to increased
mTOR activity, causing ZAP70 to be replaced by FcRγ. FcRγ then
pairs with tyrosineprotein kinase SYK rather than with ZAP70,
resulting in hyperactivation of the Tcellreceptor signalling
pathway149,150.
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Naive T cell
Nature Reviews | Rheumatology
• IL-12• IL-23
IL-21
IL-6
mDC/macrophage
Memory B cell
Plasma cell
IgE
Nucleic acid
TFH
cell
Treg
cell
TH2 cell
B cell
T cell–B cell interface at the germinal centre
FcRAntibody
ICOS
ICOSLG
CD84MHC
TCR
OX40L (TNFSF4)
OX40 (TNFRSF4)
Basophil
CD40L
CD40
CD28
CD80/CD86
SH2D1A
TLR7
Despite this hyperactivated phenotype, Tcell production of IL2
is actually impaired. Expression of IL2 in SLE T cells is
compromised by decreased levels of the transcription factor AP1 and
suppression by cAMPresponsive element modulator (CREMα)114,115.
Treatment with the mTOR inhibitor rapamycin in vitro reversed
this effect, and mTOR inhibitor treatment in vivo has been
clinically efficacious, supporting the importance of this pathway
in SLE151.
Patients with SLE also show altered Tcell subset populations.
TH17 cells are a subset of CD4+ T cells found infiltrating the
kidneys of patients with lupus nephritis, and in the skin lesions
of patients with SLE152. Polarization to TH17 involves changes to
the epigenome that can be driven by microbial products153.
Doublenegative T cells (CD4−CD8−) seem to be the primary
source of IL17 in SLE154. Doublenegative T cells are expanded
in patients with SLE as well as in lupusprone mice and are thought
to contribute to loss of tolerance155,156, as they also express
IL1β and IFNγ, and promote Bcell differentiation and antibody
production.
T cells provide more than just signals for class switching.
They represent a key checkpoint for autoreactive B cells in
SLE. Tcell–Bcell interactions are a key focus of current SLE
research because these interactions occur outside their usual
locations, in secondary lymphoid organs, and are more transient
than in healthy individuals, suggesting that the very essence of
the interaction is pathologic157,158. These aberrant Tcell–Bcell
interactions are also reflected in the somatic mutations seen in
autoantibody gene segments159. Somatic mutations reflect both
T cell help and germinal centre passage.
TFH cells specifically support Bcell differentiation by
producing IL21 and receptor engagement in the germinal centre
(FIG. 5). Expansion of the TFH cell subset has been described
in several mouse models of lupus160,161 and increased levels of TFH
cells correlate with increased disease activity and severity in
patients with SLE162–164. TFH cells can be seen within lymphoid
aggregates in kidney biopsy samples from patients with active lupus
nephritis, and activated TFH cells correlate with autoantibody
titres in these patients165,166. Emerging evidence suggests that
the expansion of TFH cells in SLE is directed by interaction with
OX40 ligand (also known as TNF ligand superfamily member 4
(TNFSF4)), which is expressed on myeloid antigenpresenting
cells167. In SLE, the expression of OX40 ligand on myeloid antigen
presenting cells is induced (via TLR7 activation) by circulating
RNAcontaining immune complexes167 (FIG. 5). The pathologically
expanded and activated TFH cell compartment markedly affects Bcell
differentiation. Enhanced antibody production and loss of tolerance
are both expected in this setting.
Treg cells have an important role in maintaining tolerance. Both
T cells and B cells are subject to Treg cell control.
Normal development of Treg cells (a subset of CD4+ cells that
inhibit and suppress autoreactive lymphocytes) is dependent on IL2.
Treatment of patients with SLE with lowdose IL2 for 5 days
caused a dramatic increase in peripheral blood CD25+FoxP3+ Treg
cells, although the clinical consequences of longterm IL2 therapy
have not yet been determined168. This study might be seen as an
important proof of principle for in vivo Tregcelldirected
therapy.
Figure 5 | Involvement of B cells in SLE. B cells are
greatly influenced by the cytokine milieu and the type of
T cell that derives from that cytokine milieu. In systemic
lupus erythematosus (SLE), B cells interact with T follicular
helper (TFH) cells at the T cell–B cell interface in
secondary lymphoid organs. The interaction revolves around
engagement of cell‑surface receptors and secretion of cytokines.
FcR, Fc receptor; mDC, myeloid dendritic cell; MHC, major
histocompatibility complex; TCR, T‑cell receptor; TH2, type 2
T helper cell; TLR, Toll‑like receptor; Treg cell, regulatory
T cell.
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B cells and autoantibody productionAlthough SLE is a
clinically heterogeneous disease, patients are nearuniversally
characterized by the presence of autoantibodies, particularly those
directed against nuclear antigens. Loss of tolerance and altered
Bcell differentiation might be genetically determined, by variants
present from birth or acquired as part of the disease process169.
Activation of B cells through the TLR pathway promotes loss of
tolerance. Mouse models have demonstrated that transitional
B cells that have recently emigrated from bone marrow are
susceptible to accelerated maturation by TLR9, which bypasses
tolerance checkpoints170. Tolerance can also be broken by Bcell
stimulation via cytokines; BAFF in particular has been implicated
in this process. BAFF antagonism in mice clearly leads to improved
selftolerance, and conversely BAFF overexpression leads to
autoimmunity171–173. Tolerance does not seem to be an allornothing
phenomenon, however. An elegant demonstration of the evolution of
autoantibodies in SLE was performed using stored plasma from
members of the armed forces. This study demonstrated progressive
development of autoantibodies over the 5–8 years preceding
onsert of the clinical manifestations of SLE174. Human studies have
clearly implicated both environmental and genetic contributions in
loss of tolerance. Early immature B cells show increased
levels of polyreactivity and autoreactivity in SLE, possibly owing
to a break in central Bcell tolerance that enables increased
numbers of autoreactive clones to reach the periphery175. Bcell
subsets are skewed to the more mature subsets, those poised to
become antibodysecreting plasma cells176. In addition,
IL10secreting B cells with regulatory capabilities show
functional impairment in SLE177,178. These observations support the
concept that Bcell development is aberrant in SLE.
B cells contribute to SLE through their responses to
antigen, regulation of other cells, and autoantibody production.
Autoantibodies contribute to SLE through the formation of immune
complexes, direct agonist or antagonist action, and by interference
with intracellular functions179. Immune complexes activate
complement and, through binding Fc receptors, drive inflammation. A
unique indirect mechanism of action occurs through binding of RNA.
The 60 kDa SSA/Ro protein binds RNA, preferring Alu retroelement
RNA. AntiRo antibodies deliver this Alu RNA to the endosomal
compartment via Fc receptors, thereby activating TLRs180. Antibody
production in patients with SLE in general seems to favour
highaffinity versions, as even anti influenza virus antibodies have
higher affinity in patients with SLE than their counterparts in
healthy controls do181. A previously unanticipated Bcell phenomenon
is the production of pathologic IgE antibodies. IgE is typically
associated with allergic responses, and little effort was made to
characterize IgE in patients with SLE until researchers showed that
half of SLE patients have IgE directed to dsDNA182. Levels of
selfreactive IgE increase with increased disease activity in
patients with SLE and the IgE immune complexes can stimulate
type I IFN in pDCs183. High total IgE concentrations have also
been described in patients with SLE184, but even in the absence
of high IgE levels, autoantibodies of the IgE isotype and
dysregulated basophils have now been observed in both mouse models
of lupus and patients with SLE185. High numbers of basophils in
mouse models of lupus contribute to a TH2 cell polarization186.
Importantly, depletion of either IgE or basophils in mice with
lupus led to diminished renal disease, supporting their mechanistic
role in SLE182,185–187 and providing support for a clinical trial
of IgEdirected therapy.
Organ-specific disease featuresNew experiments highlight that
loss of tolerance and tissue damage are two distinct processes.
Autoimmunity and kidney damage in NZM2328 lupusprone mice are
controlled by variants in Agnz1 and Cgnz1. Replacement of the
pathologic Cgnz1 allele with the normal allele did not affect the
expression of autoimmunity, but prevented kidney failure188. In
another example, when the gld.apoE−/− mouse (a lupusprone mouse
with profound atherosclerosis) was rendered IRF5deficient, it was
protected from autoimmunity but displayed increased numbers of
atherosclerotic lesions189. Thus, tissue effects are regulated
independently of tolerance. These local tissue effects, which are
also independent of haemato poietic cell influence, are major
contributors to endorgan damage in SLE. These effects have been
best described for kidney, skin, and the central nervous system
(CNS).
NephritisAmong women with SLE, approximately 30–40% of those
with European ancestry, and nearly 50% of those with AfroCaribbean
ancestry develop lupus nephritis, which is associated with
substantial morbidity and mortality190,191. Central features are
immunecomplex deposition and cell proliferation. AntidsDNA
antibodies crossreact with several renal cell types and are thought
to be central to the nephritis process. GWAS identified a
lupusnephritisassociated variant near the gene encoding the
plateletderived growth factor (PDGF) receptor192. Expression of
PDGF and its receptor is increased in kidney tissue from patients
with SLE193, and antiPDGF antibodies inhibit mesangial cell
proliferation in animal models194.
HER2 (also known as ERBB2) is also overexpressed in lupus
nephritis61 and can be upregulated by IFNs and IRF1 (REF. 61).
HER2 regulates miR26a, which in turn regulates cell
proliferation195. The HER2miR26a pathway may be of clinical
interest because antiHER2 agents have already been developed for
breast cancer treatment. Mesangial cells are capable of producing
IFNs, which may amplify local inflammatory processes196, regulate
HER2 expression, and inhibit renal progenitor cell differentiation
into podocytes, which compromises healing. In turn, mesangial
proliferation and podocyte function are controlled in SLE by local
activity of calcium/calmodulin dependent protein kinase
type IV (CaMK IV)197,198. Treatment of MRL/lpr mice with a
CaMK IV inhibitor decreased IFN production and ameliorated
nephritis199. Local cytokine production is thought to amplify the
cell infiltrate. In the MRL/lpr model, TNF and IFNγ are produced in
glomeruli before active cellular infiltrate200.
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Thus, therapies that limit tissue damage by targeting renal
parenchymal cells may also prove useful in the treatment of lupus
nephritis.
SkinCutaneous involvement is common in SLE and skin can
constitute the only organ affected. Skin lesions are seldom
lifethreatening, but represent an important source of morbidity in
SLE. Different subsets of cutaneous lupus erythematosus (which have
distinct natural histories) are classified as acute, subacute,
discoid, and intermittent (lupus erythematosus tumidus).
Ultraviolet light is a typical precipitant of an SLE flare as a
result of keratinocyte apoptosis. Immune complexes can be seen in
skin biopsies from patients with SLE (termed the ‘lupus band’) and
this finding is in fact diagnostic of SLE.
Common autoantibodies seen in patients with cutaneous forms of
SLE are antiribosomal P protein and antigalectin3. Antibodies to
Ro52 (also known as TRIM21) are also found, and deficiency of Ro52
in mice induces a lupuslike skin disease201. Why the effects of
Ro52 deficiency were localized to the skin is unclear, but Ro52 is
highly expressed in inflamed skin202, and this finding might
reflect the role of Ro52 as a nucleic acidbinding protein rather
than as having a direct role in providing protection to the
skin203. Cutaneous lesions in SLE might, therefore, reflect the
presence of specific autoantibodies, but also seem to relate to the
cutaneous dominant expression of certain proteins.
CNS diseaseCNS disease remains one of the most troubling and
puzzling clinical features of SLE. A metaanalysis indicated that
polymorphisms in genes associated with immunecomplex clearance,
such as FCGR3A and FCGR3B (encoding low affinity IgG Fc region
receptors IIIa and IIIb (FcγRIIIa and FcγRIIIb)) and ITGAM
(encoding integrin αM) are potential susceptibility genes
for neuropsychiatric lupus204. Polymorphisms in TREX1 (which
encodes 3ʹ repair exonuclease 1, also known as DNase III), have
also been associated with seizures in SLE205.
Dysfunction of the blood–brain barrier enables immunoglobulins,
cytokines, and immune cells to gain access to the brain tissue, and
is a central mechanism of neuropsychiatric lupus. The complement
system has a key role in disrupting the integrity of the
blood–brain barrier. Treatment with a C5a receptor antagonist or a
C5a antibody improved the function of the blood–brain barrier and
decreased CNS inflammation in mouse models of lupus206,207.
Complement inhibition also improved neuronal survival in these
studies206,207.
Autoantibodies, including antiphospholipid antibodies and those
targeting ribosomal P peptides, the NMDA receptor, and matrix
metalloproteinase9, could participate in the pathogenesis of
neuropsychiatric lupus through multiple mechanisms, including by
directly causing neuronal cell death208. In MRLlpr/lpr mice, CNS
disease was amplified by the cytokine TNFrelated weak inducer of
apoptosis (TWEAK, also known as TNF ligand superfamily member 12).
Mice deficient in the TWEAK receptor had better cognition and
integrity of the blood–brain barrier than their littermates209.
These studies open the door for therapeutics for CNS disease, for
which there is a critical unmet need.
ConclusionsConventional therapy for SLE has utilized broadbased
immunosuppression. Advances in our understanding of SLE
pathogenesis, as described here, will enable the development of
targeted therapies that may lead to individualized approaches to
care. Many of the advances made over the past decade are driving
interest in developing targeted therapeutics and repurposing of
drugs. Cytokines, tolerance pathways, local tissue mediators, and
epigenetic mechanisms show promise as novel targets
in SLE.
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